Children with attention-deficit/hyperactivity disorder spend more time in hyperconnected network states and less time in segregated network states as revealed by dynamic connectivity analysis.

Previous studies in children with attention-deficit/hyperactivity disorder (ADHD) have observed functional brain network disruption on a whole-brain level, as well as on a sub-network level, particularly as related to the default mode network, attention-related networks, and cognitive control-related networks. Given behavioral findings that children with ADHD have more difficulty sustaining attention and more extreme moment-to-moment fluctuations in behavior than typically developing (TD) children, recently developed methods to assess changes in connectivity over shorter time periods (i.e., "dynamic functional connectivity"), may provide unique insight into dysfunctional network organization in ADHD. Thus, we performed a dynamic functional connectivity (FC) analysis on resting state fMRI data from 38 children with ADHD and 79 TD children. We used Hidden semi-Markov models (HSMMs) to estimate six network states, as well as the most probable sequence of states for each participant. We quantified the dwell time, sojourn time, and transition probabilities across states. We found that children with ADHD spent less total time in, and switched more quickly out of, anticorrelated states involving the default mode network and task-relevant networks as compared to TD children. Moreover, children with ADHD spent more time in a hyperconnected state as compared to TD children. These results provide novel evidence that underlying dynamics may drive the differences in static FC patterns that have been observed in ADHD and imply that disrupted FC dynamics may be a mechanism underlying the behavioral symptoms and cognitive deficits commonly observed in children with ADHD.

Statistical Brain Network Analysis.

The recent fusion of network science and neuroscience has catalyzed a paradigm shift in how we study the brain and led to the field of brain network analysis. Brain network analyses hold great potential in helping us understand normal and abnormal brain function by providing profound clinical insight into links between system-level properties and health and behavioral outcomes. Nonetheless, methods for statistically analyzing networks at the group and individual levels have lagged behind. We have attempted to address this need by developing three complementary statistical frameworks-a mixed modeling framework, a distance regression framework, and a hidden semi-Markov modeling framework. These tools serve as synergistic fusions of statistical approaches with network science methods, providing needed analytic foundations for whole-brain network data. Here we delineate these approaches, briefly survey related tools, and discuss potential future avenues of research. We hope this review catalyzes further statistical interest and methodological development in the field.

Contrasting topologies of synchronous and asynchronous functional brain networks.

We generated asynchronous functional networks (aFNs) using a novel method called optimal causation entropy (oCSE) and compared aFN topology to the correlation-based synchronous functional networks (sFNs) which are commonly used in network neuroscience studies. Functional magnetic resonance imaging (fMRI) time series from 212 participants of the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) study were used to generate aFNs and sFNs. As a demonstration of how aFNs and sFNs can be used in tandem, we used multivariate mixed effects models to determine whether age interacted with node efficiency to influence connection probabilities in the two networks. After adjusting for differences in network density, aFNs had higher global efficiency but lower local efficiency than the sFNs. In the aFNs, nodes with the highest outgoing global efficiency tended to be in the brainstem and orbitofrontal cortex. aFN nodes with the highest incoming global efficiency tended to be members of the Default Mode Network (DMN) in sFNs. Age interacted with node global efficiency in aFNs and node local efficiency in sFNs to influence connection probability. We conclude that the sFN and aFN both offer information about functional brain connectivity which the other type of network does not.

Feasibility of Remote Administration of the Uniform Data Set-Version 3 for Assessment of Older Adults With Mild Cognitive Impairment and Alzheimer's Disease.

OBJECTIVE: Assess the feasibility and concurrent validity of a modified Uniform Data Set version 3 (UDSv3) for remote administration for individuals with normal cognition (NC), mild cognitive impairment (MCI), and early dementia. METHOD: Participants (N = 93) (age: 72.8 [8.9] years; education: 15.6 [2.5] years; 72% female; 84% White) were enrolled from the Wake Forest ADRC. Portions of the UDSv3 cognitive battery, plus the Rey Auditory Verbal Learning Test, were completed by telephone or video within ~6 months of participant's in-person visit. Adaptations for phone administration (e.g., Oral Trails for Trail Making Test [TMT] and Blind Montreal Cognitive Assessment [MoCA] for MoCA) were made. Participants reported on the pleasantness, difficulty, and preference for each modality. Staff provided validity ratings for assessments. Participants' remote data were adjudicated by cognitive experts blinded to the in person-diagnosis (NC [N = 44], MCI [N = 35], Dementia [N = 11], or other [N = 3]). RESULTS: Remote assessments were rated as pleasant as in-person assessments by 74% of participants and equally difficult by 75%. Staff validity rating (video = 92%; phone = 87.5%) was good. Concordance between remote/in-person scores was generally moderate to good (r = .3 -.8; p < .05) except for TMT-A/OTMT-A (r = .3; p > .05). Agreement between remote/in-person adjudicated cognitive status was good (k = .61-.64). CONCLUSIONS: We found preliminary evidence that older adults, including those with cognitive impairment, can be assessed remotely using a modified UDSv3 research battery. Adjudication of cognitive status that relies on remotely collected data is comparable to classifications using in-person assessments.

Brain Network Analysis: A Review on Multivariate Analytical Methods.

Despite the explosive growth of neuroimaging studies aimed at analyzing the brain as a complex system, critical methodological gaps remain to be addressed. Most tools currently used for analyzing network data of the brain are univariate in nature and are based on assumptions borne out of previous techniques not directly related to the big and complex data of the brain. Although graph-based methods have shown great promise, the development of principled multivariate models to address inherent limitations of graph-based methods, such as their dependence on network size and degree distributions, and to allow assessing the effects of multiple phenotypes on the brain and simulating brain networks has largely lagged behind. Although some studies have been made in developing multivariate frameworks to fill this gap, in the absence of a "gold-standard" method or guidelines, choosing the most appropriate method for each study can be another critical challenge for investigators in this multidisciplinary field. Here, we briefly introduce important multivariate methods for brain network analyses in two main categories: data-driven and model-based methods. We discuss whether/how such methods are suited for examining connectivity (edge-level), topology (system-level), or both. This review will aid in choosing an appropriate multivariate method with respect to variables such as network type, number of subjects and brain regions included, and the interest in connectivity, topology, or both. This review is aimed to be accessible to investigators from different backgrounds, with a focus on applications in brain network studies, though the methods may be applicable in other areas too. Impact statement As the U.S. National Institute of Health notes, the rich biomedical data can greatly improve our knowledge of human health if new analytical tools are developed, and their applications are broadly disseminated. A major challenge in analyzing the brain as a complex system is about developing parsimonious multivariate methods, and particularly choosing the most appropriate one among the existing methods with respect to the study variables in this multidisciplinary field. This study provides a review on the most important multivariate methods to aid in helping the most appropriate ones with respect to the desired variables for each study.

A mixed-modeling framework for whole-brain dynamic network analysis.

The emerging area of dynamic brain network analysis has gained considerable attention in recent years. However, development of multivariate statistical frameworks that allow for examining the associations between phenotypic traits and dynamic patterns of system-level properties of the brain, and drawing statistical inference about such associations, has largely lagged behind. To address this need we developed a mixed-modeling framework that allows for assessing the relationship between any desired phenotype and dynamic patterns of whole-brain connectivity and topology. This novel framework also allows for simulating dynamic brain networks with respect to desired covariates. Unlike current tools, which largely use data-driven methods, our model-based method enables aligning neuroscientific hypotheses with the analytic approach. We demonstrate the utility of this model in identifying the relationship between fluid intelligence and dynamic brain networks by using resting-state fMRI (rfMRI) data from 200 participants in the Human Connectome Project (HCP) study. We also demonstrate the utility of this model to simulate dynamic brain networks at both group and individual levels. To our knowledge, this approach provides the first model-based statistical method for examining dynamic patterns of system-level properties of the brain and their relationships to phenotypic traits as well as simulating dynamic brain networks.